Development of a Scalable Asymmetric Process for the Synthesis of Selective PDE4B Inhibitor Nerandomilast (BI 1015550),Organic Process Research & Development

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Development of a Scalable Asymmetric Process for the Synthesis of Selective PDE4B Inhibitor Nerandomilast (BI 1015550)
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-09-05 , DOI: 10.1021/acs.oprd.4c00309
Rogelio P. Frutos ₁ , Thomas G. Tampone ₁ , Frank Gerstmann ₂ , Dirk Weber ₂ , Tobias Brodmann ₂ , Robert Hagenkötter ₂ , Jocelyn Abella ₃ , Bing-Shiou Yang ₃ , Jason Mulder ₁ , Sonia Rodriguez ₁ , Heewon Lee ₁ , Joe Gao ₃ , Jinhua J. Song ₁

Affiliation

A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective S_NAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).

中文翻译：

开发用于合成选择性 PDE4B 抑制剂 Nerandomilast 的可扩展不对称工艺 (BI 1015550)

Nerandomilast ( 1 , BI 1015550) 是一种选择性 PDE4B 抑制剂，具有治疗呼吸系统疾病的潜在治疗特性，其强大且可扩展的合成工艺已在中试工厂以公斤级规模开发和实施。该方法的关键方面包括通过(1-氨基环丁基)甲醇 ( 6 ) 和 2,4-二氯-6,7-二氢噻吩并[3,2- d ]嘧啶 ( 5 ) 之间的区域选择性_SNA Ar 反应，一种新的 5-氯-2- 聚合合成(哌啶-4-基)嘧啶( 3 )通过Suzuki偶联和高度对映选择性硫化物氧化得到手性非外消旋( R )-2-氯-4-((1-(羟甲基)环丁基)氨基)- 6,7-二氢噻吩并[3,2- d ]嘧啶5-氧化物( 2 )。

更新日期：2024-09-05

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